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研究生: 姜秉均
Chiang, Bing-Juin
論文名稱: 尿道結石與膀胱過動症治療策略與研究的發展
Treatment Strategies and Studies of Urolithiasis and Overactive Bladder
指導教授: 鄭劍廷
Chien, Chiang-Ting
學位類別: 博士
Doctor
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2018
畢業學年度: 106
語文別: 中文
論文頁數: 51
中文關鍵詞: 氧化壓力結石體外震波碎石對苯二胺排尿障礙
英文關鍵詞: oxidative stress, urolithiasis, ESWL, para-phenylenediamine, LUTS
DOI URL: http://doi.org/10.6345/DIS.NTNU.SLS.017.2018.D01
論文種類: 學術論文
相關次數: 點閱:152下載:5
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  • 過多的氧化壓力在許多泌尿科學方面的疾病愈症狀扮演著重要的腳色,例如泌尿系統癌症、尿路結石、不孕、性功能障礙、慢性腎臟病變、膀胱過動症、與其他下泌尿路排尿障礙等疾病。
    在過去的臨床與基礎研究可發現,尿路結石與氧化壓力的產生可能互為因果,且尿路結石在產生與排除的過程中有可造成泌尿道的損傷,導致體外震波碎石的治療效果降低;許多臨床文獻利用無顯影劑輔助之電腦斷層來判斷患者的腰側疼痛是否為尿路結石所引起之腎絞痛,也利用結石在電腦斷層上的特性來判斷輸尿管結石是否能成功以體外震波碎石治療,但電腦斷層並非判斷病人是否罹患尿路結石疾病的必要臨床影像工具,且對於體外震波碎石也無法在術中提供即時定位的功能,另外在台灣健保審核結石疾病之給付時也並非必要之檢查項目,故目前許多文獻利用結石於電腦斷層上的特徵來做為手術成功與失敗的預測因子,無法完整應用於實際臨床上的判斷,故本論文之第一個研究部分,利用生物統計方法找出無電腦斷層輔助之體外震波碎石手術成功的預測因子,期待結果能增進體外震波碎石手術之成功率,我們並進一步利用測定結石患者尿液的氧化壓力,比較是否較一般人為高。
    對苯二胺為頭髮染劑與皮革染劑之常見的成分,對苯二胺與其具有毒性的代謝物能夠產生過量的過氧化物,而在過去的臨床與動物實驗文獻中已證明了於膀胱內若由於各種疾病引起過度的氧化壓力,將會導致組織的受損與膀胱的失能,因此我們於本論文的第二個基礎研究部分,將嘗試長期給予老鼠低劑量的對苯二胺,觀察膀胱受損的狀況,然後進一步應用合成的擬含鎳超氧化物歧化酶治療對苯二胺引起之膀胱失能。

    The excessive reactive oxygen species (ROS) play an important part in development of urological diseases or conditions, such as cancer, urolithiasis, infertility, sexual dysfunction, chronic kidney disease, overactive bladder, and other lower urinary tract symptoms.

    Among previous clinical and basic researches, urolithiasis and oxidative stress interact as both cause and effect. Generation and passing of urolithiasis might cause urinary tract injuries, which might decrease efficacy of extracorporeal shock wave lithotripsy (ESWL). The existent studies explored the utility of Non-contrast computed tomography (NCCT) on diagnosis of urolithiasis and defining predictors of successful ESWL. However, NCCT is not always performed clinically if the diagnosis of ureteral calculi has been confirmed by other radiographics. NCCT is of no help for real-time localization of calculi. NCCT is also unnecessary prior to ESWL for National Taiwan Health Insurance medical claims reviews. Thus, there is a discrepancy between the accumulated evidence of predictors based on NCCT and those available in clinical practice. The first clinical study was to find biometrical predictors for the success of ESWL without assistance of NCCT. The results would enhance the clinical decision making and successful rates of stone clearance. Furthermore, we define existence of the free radicals in urine with electron paramagneic resonance.

    Para-phenylenediamine (PPD) is a common ingredient in hair and leather dyes. PPD and its toxic metabolites induce excess reactive oxygen species formation. Oxidative stress from varies etiology upregulates tissue-damage marker compounds and induces bladder dysfunction in clinical and animal studies. We hypothesized chronic PPD exposure results in bladder injuries. Furthermore, we evaluated the therapeutic effect of synthetic nickel-containing superoxide dismutase mimics on PPD-induced bladder dysfunction rat models.

    第一章 續論及文獻探討 9 1.1無電腦斷層掃描輔助時體外震波碎石成功率的預測因子與結石患者尿液自由基的判定 9 1.1.1尿路結石的形成與氧化壓力之間的關聯性 9 1.1.2老化及氧化壓力與輸尿管泌尿上皮與平滑肌肉受損可能的關聯性 9 1.1.3無顯影劑電腦斷層掃描對於輸尿管結石相關參數的判讀的應用與限制 10 1.1.4 體外震波碎石術成功治療輸尿管結石預測因子的判定 11 1.2合成含鎳超氧化物歧化酶模擬物對苯二胺誘發的膀胱功能障礙於大鼠中的療效 11 1.2.1膀胱過動症/下泌尿道症候群與氧化壓力之間的關聯性 11 1.2.2對苯二胺的臨床重要性 12 1.2.3對苯二胺與氧化壓力之間的關聯性 12 1.2.4合成含鎳超氧化物歧化酶模擬物對治療對苯二胺引致的膀胱功能障礙療效的理論依據 13 第二章 研究材料及方法 15 2.1無電腦斷層掃描輔助時體外震波碎石成功率的預測因子與結石患者尿液自由基的判定 15 2.1.1研究方案 15 2.1.2電子順磁共振光譜 15 2.1.3統計分析 16 2.2合成含鎳超氧化物歧化酶模擬物對苯二胺誘發的膀胱功能障礙於大鼠中的療效 16 2.2.1實驗動物與分組 16 2.2.2合成含鎳超氧化物歧化酶模擬物的製備 17 2.2.3血液動力學和膀胱內壓參數 17 2.2.4膀胱微循環測定 18 2.2.5體外活性氧類之活性 19 2.2.6體內膀胱表面的超氧自由基生成 19 2.2.7原位檢測氧化壓力、炎症、自噬作用作用、細胞凋亡和細胞焦亡 20 2.2.8細胞凋亡、自噬作用作用和細胞焦亡的蛋白質表現量 21 2.2.9統計分析 21 第三章 结果 22 3.1無電腦斷層掃描輔助時體外震波碎石成功率的預測因子與結石患者尿液自由基的判定 22 3.1.1 所有病患、治療成功組和治療失敗組的人口統計資料 22 3.1.2多變量分析中預測因子的判定 22 3.1.3電子順磁共振光譜對於自由基的測定 23 3.2評估合成含鎳超氧化物歧化酶模擬物對苯二胺誘發的膀胱功能障礙於大鼠中的療效 23 3.2.1合成含鎳超氧化物歧化酶模擬物有效改善對苯二胺引致的膀胱過動症 23 3.2.2 對苯二胺誘發的膀胱缺血、炎症反應和血液中活性氧類的產生 23 3.2.3合成含鎳超氧化物歧化酶模擬物減弱對苯二胺誘發的膀胱炎症、氧化損傷、細胞凋亡、自噬作用和細胞焦亡 24 第四章 討論與結論 25 4.1無電腦斷層掃描輔助時體外震波碎石成功率的預測因子與結石患者尿液自由基的判定 25 4.2評價合成含鎳超氧化物歧化酶模擬物對苯二胺誘發的膀胱功能障礙於大鼠中的療效 28 參考文獻 43 表格 31 表1病患相關資料的統計表格-治療成功與失敗的單變數分析比較表 31 表2結石廓清成功率預測因子的多變數分析 32 表3代謝箱的相關指標 33 表4尿路動力學檢查的相關指標 34 圖片 35 圖1電子順磁共振光譜對於自由基的測定 35 圖2含鎳超氧化物歧化酶模擬物的化學構造 36 圖3排尿參數圖形 37 圖4含鎳超氧化物歧化酶模擬物(WCT003與WCT006)對於對苯二胺引起膀胱過動在尿路動力學上的治療效果 38 圖5急性對苯二胺暴露後對於膀胱病理與微循環的變化 39 圖6體外PPD對於尿液與血液裡H2O2 and HOCl活性的影響 40 圖7 WCT003與WCT006對於對苯二胺引起膀胱氧化壓力傷害的治療效果 41 圖8 WCT003與WCT006對於PPD引起之LC3 II、PARP、與 caspase 1蛋白質的表現量的影響 42

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